1,6-naphthyridine-2(1H)-ones and their use as cardiotonic agents

ABSTRACT

5-X-7-R&#39;-1,6-Naphthyridine-2(1H)-ones (formula II) or salts thereof, where X is bromo, chloro or hydrazino and R&#39; is hydrogen or methyl, which are useful as cardiotonic agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of copending applicationsSer. No. 737,129, now abandoned filed May 23, 1985, and Ser. No.816,591, filed Jan. 6, 1986, the latter a continuation-in-part ofcopending application Ser. No. 811,040, now abandoned filed Dec. 19,1985, in turn, a continuation-in-part of copending application Ser. No.765,900, now abandoned filed Aug. 14, 1985, in turn, acontinuation-in-part of its copending application Ser. No. 695,603,filed Jan. 28, 1985 and now abandoned.

Copending application Ser. No. 816,519 discloses and claims the5-[1H-(5-membered-N-aromatic-heteryl)-1-yl]-1,6-naphthyridin-2(1H)-onesof formula I herein-below, which are prepared from compounds disclosedand claimed herein, and also their cardiotonic use.

BACKGROUND OF THE INVENTION (a) Field of the Invention

This invention relates to 5-(halo orhydrazino)-1,6-naphthyridin-2(1H)-ones, the cardiotonic use of the5-halo compounds, their preparation and intermediates therefor, andtheir use as intermediates in preparing5-[1H-(5-membered-N-aromatic-heteryl)-1-yl]-1,6-naphthyridin-2(1H)-ones.

(b) Information Disclosure Statement

Lesher and Singh in U.S. Pat. No. 4,415,580, issued Nov. 15, 1983, showas cardiotonic agents 5-(lower-alkyl)-1,6-naphthyridin-2(1H)-ones (I)and their preparation by reacting a5-(lower-alkanoyl)-6-methyl-2(1H)-pyridinone withdi-(lower-alkyl)formamide di-(lower-alkyl) acetal to produce5-(lower-alkanoyl)-6-[2-(di-lower-alkylamino)ethenyl]-2(1H)-pyridinone(II) and reacting II with formamidine or ammonia or salt thereof toproduce I.

Czuba et al., Pol. J. Chem. 52, 2369-76 (1978), show as intermediates4-bromo-1,6-naphthyridin-2(1H)-one and4-hydrazino-1,6-naphthyridin-2(1H)-one. This reference also shows thepreparation of 4-bromo-1,6-naphthyridin-2(1H)-one by heating2,4-dibromo-1,6-naphthyridine with 20% hydrobromic acid and thepreparation of 4-hydrazino-1,6-naphthyridin-2(1H)-one by heating4-bromo-1,6-naphthyridin-2(1H)-one with hydrazine.

Paudler et al., J. Heterocyclic Chem. 2 (4), 393-8 (1965), show thesynthesis and NMR spectra of various 4-substituted-1,6-naphthyridines,for example, the reaction of 4-hydroxy-1,6-naphthyridine with POBr₃ orPOCl₃ to obtain 4-bromo-1,6-naphthyridine or 4-chloro-1,6-naphthyridine,respectively. Also shown is the reaction of 4-bromo-1,6-naphthyridinewith dimethylamine to produce 4-dimethylamino-1,6-naphthyridine and thereaction 4-chloro-1,6-naphthyridine with piperidine or hydrazine toproduce 4-(1-piperidinyl)-1,6-naphthyridine or4-hydrazino-1,6-naphthyridine, respectively.

Rooney et al. U.S. Pat. No. 3,993,656, issued Nov. 23, 1976, showsvarious substituted-1,8-naphthyridin-2(1H)-ones having bronchodilatingand hypotensive properties, including6-(2-imidazolyl)-1,8-naphthyridin-2(1H)-one and its preparation from2-amino-6-(2-imidazolyl)-1,8-naphthyridine.

SUMMARY OF THE INVENTION

In a composition of matter aspect, the invention resides in5-X-7-R'-1,6-naphthyridin-2(1H)-one having the formula II ##STR1## orpharmaceutically acceptable acid-addition or cationic salt thereof,where X is bromo, chloro or hydrazino and R' is hydrogen or methyl. Thecompounds of formula II where X is bromo or chloro, are useful ascardiotonic agents, as determined by standard pharmacologicalprocedures, and also are useful as intermediates for preparing the5-[1H-(5-membered-N-aromatic-heteryl)-1-yl]-7-R'-1,6-naphthyridin-2(1H)-onesuseful as cardiotonic agents and having the formula I ##STR2## oracid-addition or cationic salt thereof, where R is hydrogen, halo orlower-alkyl, R' is hydrogen or methyl, R₁ is hydrogen, lower-alkyl,hydroxymethyl, halo, trifluoromethyl, nitro or phenyl, Z is N, C--H,C-(loweralkyl), C-halo, C-hydroxymethyl or C-phenyl, and Y is N, C--H,C-halo, C-(lower-alkyl) or C--NO₂, at least one of Y or Z being N. Whenused as intermediates, the compounds of formula II where X is bromo arepreferred. The compounds of formula II where X is hydrazino are usefulas intermediates for preparing the compounds of formula I where Y is Nand Z is C--H.

Another composition aspect of the invention resides in the cardiotoniccomposition for increasing cardiac contractility which comprises apharmaceutically acceptable carrier and, as the active componentthereof, a cardiotonically effective amount of5-X-7-R'-1,6-naphthyridin-2(1H)-one having the formula II orpharmaceutically acceptable acid-addition or cationic salt thereof,where X is bromo or chloro and R' is hydrogen or methyl.

A method aspect of the invention resides in the method for increasingcardiac contractility in a patient requiring such treatment whichcomprises administering orally or parenterally in a solid or liquiddosage form to such patient a cardiotonically effective amount of5-X-7-R'-1,6-naphthyridin-2(1H)-one having the formula II orpharmaceutically acceptable acid-addition or cationic salt thereof,where X is bromo or chloro and R' is hydrogen or methyl.

In another composition of matter aspect, the invention resides in1,6-dihydro-2-[2-(di-lower-alkylamino)ethenyl]-6-oxo-3-pyridinecarbonitrilehaving the formula III ##STR3## and acid-addition salt thereof, where R¹and R² are each lower-alkyl. The compounds of formula III are useful asintermediates in the preparation of 5-bromo(orchloro)-1,6-naphthyridin-2(1H)-one of formula II where R' is hydrogen.

A process aspect of the invention resides in the process which comprisesreacting hydrogen bromide or hydrogen chloride with1,6-dihydro-2-[2-(di-lower-alkylamino)-ethenyl-]-6-oxo-3-pyridinecarbonitrileof formula III to produce 5-bromo(or chloro)-1,6-naphthyridin-2(1H)-oneof formula II above where R' is hydrogen and X is bromo or chloro andthen reacting 5-bromo(or chloro)-1,6-naphthyridin-2(1H)-one with1H-(5-membered-N-aromatic)heteryl compound having the formula IV##STR4## where Y, Z, R₁ and R are defined as in formula I, to producethe5-[1H-(5-membered-N-aromatic-heteryl)-1-yl]-1,6-naphthyridin-2(1H)-oneof formula I where R' is hydrogen.

Another process aspect of the invention resides in the process whichcomprises reacting 1,6-dihydro-2-methyl-6-oxo-3-pyridinecarbonitrilewith bis(di-lower-alkylamino)-t-butoxymethane of formula V

    (R.sub.1 R.sub.2 N).sub.2 CHOC(CH.sub.3).sub.3             ( 3)

to produce1,6-dihydro-2-[2-(di-lower-alkylamino)-ethenyl]-6-oxo-3-pyridinecarbonitrileof formula III.

Another process aspect of the invention resides in the process whichcomprises reacting 5-hydrazino-7-R'-1,6-naphthyridin-2(1H)-one offormula II where X is hydrazino with 1,1,3,3-tetramethoxypropane toproduce 5-(1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one of formula Iwhere Y is N, Z is C--H, R₁ and R are each hydrogen and R' is hydrogenor methyl.

In another composition of matter aspect, the invention resides in2-[2-(di-lower-alkylamino)-1-propenyl]-6-methoxy-3-pyridinecarbonitrilehaving the formula IIIa ##STR5## and acid-addition salt thereof, whereR₂ and R₃ are each lower-alkyl. This compound is useful as anintermediate for preparing the compound of formula II where X is bromoor chloro and R' is methyl.

In another process aspect, the invention resides in the process whichcomprises reacting hydrogen bromide or hydrogen chloride with2-[2-(di-lower-alkylamino)-1-propenyl]-6-methoxy-3-pyridinecarbonitrileto produce 5-(bromo or chloro)-2-methoxy-7-methyl-1,6-naphthyridine,treating said 2-methoxy compound with aqueous sodium or potassiumhydroxide solution to produce 5-(bromo orchloro)-7-methyl-1,6-naphthyridin-2(1H)-one and then reacting 5-bromo(orchloro)-7-methyl-1,6-naphthyridin-2(1H)-one with1H-(5-membered-N-aromatic)-heteryl compound having the formula IV##STR6## to produce the5-[1H-(5-membered-N-aromatic-heteryl)-1-yl]-7-methyl-1,6-naphthyridin-2(1H)-onehaving the formula I where R is hydrogen, halo or lower-alkyl, R₁ ishydrogen, lower-alkyl, hydroxymethyl, halo, trifluoromethyl, nitro orphenyl, Z is N, C--H, C-(lower-alkyl), C-halo, C-hydroxymethyl orC-phenyl, and Y is N, C--H, C-halo, C-(lower-alkyl) or C--NO₂, at leastone of Y or Z being N.

DETAILED DESCRIPTION INCLUSIVE OF PREFERRED EMBODIMENTS

Preferred compounds of formula II are those where X is bromo and R' ishydrogen or methyl and salts thereof.

Preferred compounds having formula III or IIIa are those where R₁ and R₂are each methyl and acid-addition salts thereof.

Preferred compounds having formula I are those where Y is CH when Z isN, R₁ and R are each hydrogen or methyl and R' is hydrogen, or Y is Nwhen Z is CH, R' is hydrogen and, R₁ and R are each hydrogen, or Y and Zare each N when R', R₁ and R are each hydrogen.

The term "lower-alkyl" as used herein, e.g., one of the meanings for Ror R₁ in formula I, as C-(lower-alkyl) for one of the meanings of Z or Yin formula I, or as the meaning of R₂ or R₃ in formulas III, IIIa and IVmeans alkyl radicals having from 1 to 4 carbon atoms which can bearranged as straight or branched chains, illustrated by methyl, ethyl,n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl and isobutyl.

The term "halo" as used herein, e.g., as one of the meanings for R or R₁in formula I or in C-halo as one of the meanings for Y or Z in formulaI, preferably means bromo or chloro.

The compounds of formulas I, II, III and IIIa are useful both in thefree base form and in the form of acid-addition salts, and, both formsare within the purview of the invention. The acid-addition salts aresimply a more convenient form for use; and in practice, use of the saltform inherently amounts to use of the base form. The acids which can beused to prepare the acid-addition salts of the compounds of formulas I,II, III and IIIa include preferably those which produce, when combinedwith the free base, pharmaceutically acceptable salts, that is, saltswhose anions are relatively innocuous to the animal organism inpharmaceutical doses of the salts, so that the beneficial cardiotonicproperties inherent in the free base (I and II) are not vitiated by sideeffects ascribable to the anions. Appropriate pharmaceuticallyacceptable salts within the scope of the invention are those derivedfrom mineral acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, phosphoric acid and sulfamic acid; and organic acids such aslactic acid, acetic acid, citric acid, tartaric acid, methanesulfonicacid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,cyclohexylsulfamic acid, quinic acid, and the like, giving thehydrochloride, hydrobromide, sulfate, phosphate, sulfamate, lactate,acetate, citrate, tartrate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate,respectively.

The acid-addition salts of said basic compounds of formulas I and II areprepared either by dissolving the free base in aqueous oraqueous-alcohol solution or other suitable solvents containing theappropriate acid and isolating the salt by evaporating the solution, orby reacting the free base and acid in an organic solvent, in which casethe salt separates directly or can be obtained by concentration of thesolution. The acid-addition salts of said basic compounds of formulasIII and IIIa are prepared as above by dissolving the free base in anon-aqueous solvent, e.g., methanol or ethanol, or other suitablesolvent.

Although pharmaceutically acceptable salts of said basic compounds offormulas I, II, III and IIIa are preferred, all acid-addition salts arewithin the scope of the invention. All acid-addition salts are useful assources of the free base form even if the particular salt per se isdesired only as an intermediate product as for example when the salt isformed only for purposes of purification or identification, or when itis used as an intermediate in preparing a pharmaceutically acceptablesalt by ion exchange procedures.

Other pharmaceutically acceptable salts of said compound of formulas Iand II are those cationic salts derived from strong inorganic or organicbases, e.g., sodium hydroxide, potassium hydroxide, monobasic or dibasiclower-alkylamines, tetra-(lower-alkyl)ammonium hydroxides.

The molecular structures of the compounds of formulas I, II, III, IIIaand IV were assigned on the basis of evidence provided by infrared,ultraviolet, nuclear magnetic resonance and mass spectra, by thecorrespondence of calculated and found values for the elementalanalyses, and by their method of preparation.

The manner of making and using the instant invention will now begenerally descibed so as to enable a person skilled in the art ofpharmaceutical chemistry to make and use the same.

The reaction of 1,6-dihydro-2-methyl-6-oxo-3-pyridinecarbonitrile withbis(di-lower-alkylamino)-t-butoxymethane of formula V to produce2-[2-(di-lower-alkylamino)ethenyl]-1,6-dihydro-6-oxo-3-pyridinecarbonitrile of formula III is carried outby heating the reactants at about 100° C. to 160° C., preferably in asuitable aprotic solvent. The reaction is conveniently run by refluxingthe reactants in dimethylformamide or dioxane (p-dioxane), preferablyusing bis(dimethylamino)-t-butoxymethane.

The intermediate bis(di-lower-alkylamino)-t-butoxymethanes of formula Vare known compounds or are prepared by conventional means.

Alternatively, the compounds of formula III where the lower-alkyl groupsR₂ and R₃ have from 2 to 4 carbon atoms are conveniently prepared byrefluxing the compound of formula III where R₂ and R₃ are each methylwith an excess of the appropriate amine of the formula R₂ R₃ NH inmethanol.

The preparation of said intermediate1,6-dihydro-2-methyl-6-oxo-3-pyridinecarbonitrile is shown in Ciba-GeigyAG German Patent Publication No. 2,256,288, published May 24, 1973.3-Aminocrotononitrile is reacted with 3-ethoxyacrylic acid chloride at-15° C. to -10° C. in a mixture of pyridine, tetrahydrofuran anddimethylformamide, and then the reaction mixture is treated with water.As shown hereinbelow, 1,6-dihydro-2-methyl-6-oxo-3-pyridinecarbonitrilewas conveniently prepared by refluxing a mixture of3-aminocrotrononitrile and methyl propiolate in dimethylformamide.

The reaction of 6-methoxy-2-methyl-3-pyridinecarbonitrile withdi-(lower-alkyl)acetamide dimethyl acetal to produce2-[2-(di-lower-alkylamino)-1-propenyl)]-6-methoxy-3-pyridinecarbonitrileof formula IIIa is carried out by heating the reactants in a suitableaprotic solvent, preferably dimethylformamide, at about 120°-140° C.,preferably using dimethylacetamide dimethyl acetal.

The reaction of hydrogen bromide or hydrogen chloride with2-[2-(di-lower-alkylamino)ethenyl]-1,6-dihydro-6-oxo-3-pyridine-carbonitrileof formula III to produce 5-bromo(or chloro)-1,6-naphthyridin-2(1H)-oneof formula II where X is bromo or chloro and R' is hydrogen is carriedout by bubbling gaseous hydrogen bromide or hydrogen chloride into achilled and stirred solution containing III in a suitable solvent, e.g.,a mixture of chloroform and acetic acid, and then stirring the reactionmixture at room temperature.

The reaction of hydrogen bromide or hydrogen chloride with2-[2-(di-lower-alkylamino)-1-propenyl]-6-methoxy-3-pyridinecarbonitrileof formula IIIa to produce 5-(bromo orchloro)-2-methoxy-7-methyl-1,6-naphthyridine is carried out as describedin the immediately preceding paragraph and then said 2-methoxy compoundis treated with aqueous sodium or potassium hydroxide solution at roomtemperature to produce 5-(bromo orchloro)-7-methyl-1,6-naphthyridin-2(1H)-one of formula II where X isbromo or chloro and R' is methyl.

The reaction of 5-bromo(or chloro)-7-R'-1,6-naphthyridin-2(1H)-one witha 1H-(5-membered-N-aromatic)-heteryl compound of formula IV to producethe5-[1H-(5-membered-N-aromatic-heteryl)-1-yl]-7-R'-1,6-naphthyridin-2(1H)-oneof formula I is carried out by heating the reactants at about 125° C. to225° C., preferably about 140° C. to 180° C. in a suitable inert solventin the presence or absence of an acid-acceptor. Illustrative solventsare dimethylformamide, N-methylpyrrolidinone, and illustrativeacid-acceptors are anhydrous potassium carbonate, sodium methoxide,sodium hydride, and the like. The reaction is preferably run usingN-methylpyrrolidin-one as solvent and using a two-to-four fold excess,preferably three fold excess, of 1H-(5-membered-N-aromatic)-heterylcompound of formula IV per mole of5-bromo-7-R'-1,6-naphthyridin-2(1H)-one in the absence of anacid-acceptor.

The intermediate 1H-(5-membered-N-aromatic)-heteryl compounds of formulaIV are known compounds which are prepared by conventional means or arecommercially available.

The reaction of 5-hydrazino-7-R'-1,6-naphthyridin-2(1H)-one with1,1,3,3-tetramethoxypropane to produce5-(1H)-pyrazol-1-yl)-7-R'-1,6-naphthyridin-2(1H)-one is carried out byheating the reactants in a suitable solvent, e.g., ethylene glycol, atabout 150° C. to 200° C., preferably about 160° C. to 180° C.

5-Hydrazino-7-R'-1,6-naphthyridin-2(1H)-one is conveniently formed byheating 5-bromo(or chloro)-7-R'-1,6-naphthyridin-2(1H)-one withhydrazine hydrate.

The following examples will further illustrate the invention without,however, limiting it thereto.

1. 2-[2-(Dimethylamino)ethenyl]-1,6-dihydro-6-oxo-3-pyridinecarbonitrile

To a stirred mixture containing 6.7 g of1,6-dihydro-2-methyl-6-oxo-3-pyridinecarbonitrile in 100 ml ofdimethylformamide was quickly added 11.5 ml ofbis(dimethylamino)-t-butoxymethane and the reaction mixture was heatedwith stirring for 3 hours at 110° C. After a tlc analysis had shown someof the starting material still present, another 2.3 ml ofbis(dimethylamino)-t-butoxymethane was added, the reaction mixture washeated with stirring to reflux for 90 minutes, and then allowed to coolto room temperature and stand overnight. The mixture was chilled and theseparated product was collected, washed with chilled ethanol and driedin a vacuum oven at 90° C. to yield 8.2 g of2-[2-(dimethylamino)ethenyl]-1,6-dihydro-6-oxo-3-pyridinecarbonitrile,m.p. 298°-300° C.

The above intermediate 1,6-dihydro-2-methyl-6-oxo-3-pyridinecarbonitrilewas prepared as follows: a mixture containing 85%3-amino-2-butenenitrile and 8.4 g of methyl propiolate was heated on asteam bath for about 15 minutes whereupon a vigorous exothermic reactionensued. External heating was stopped until the reaction subsided. To thereaction mixture was added 25 ml of dimethylformamide and the reactionmixture was refluxed for 8 hours, allowed to cool to room temperatureand then stand overnight. The separated solid was collected, washed withethanol and dried in a vacuum oven at 90° C. to yield 3.4 g of1,6-dihydro-2-methyl-6-oxo-3-pyridinecarbonitrile, m.p. >300° C.

Acid-addition salts of2-[2-(dimethylamino)ethenylyl]-1,6-dihydro-6-oxo-3-pyridinecarbonitrileare conveniently prepared by adding to a mixture of 2 g of2-[2-(dimethylamino)ethenyl]-1,6-dihydro-6-oxo-3-pyridinecarbonitrile inabout 40 ml of methanol or ethanol the appropriate acid, e.g.,methanesulfonic acid, concentrated sulfuric acid, concentratedphosphoric acid, to a pH of about 2 to 3, chilling the mixture afterpartial evaporation and collecting the precipitate, e.g.,dimethanesulfonate, sulfate, phosphate, respectively.

2. 2-2-(Diethylamino)ethenyl]-1,6-dihydro-6-oxo-3-pyridinecarbonitrile,m.p. 218°-220° C., was prepared by refluxing2-[2-(dimethylamino)ethenyl]-1,6-dihydro-6-oxo-3-pyridinecarbonitrilewith a 3 to 4 molar excess of diethylamine for about 70 hours; thereaction mixture was allowed to cool; and, the precipitated product wascollected, recrystallized from isopropyl alcohol and dried in a vacuumoven at 90° C.

Also,2-[2-(diethylamino)ethenyl]-1,6-dihydro-6-oxo-3-pyridinecarbonitrile canbe prepared following the procedure described in Example 1 using a molarequivalent quantity of bis(diethylamino)-t-butoxymethane in place ofbis(dimethylamino)-t-butoxymethane.

3.2-[2-(Di-n-propylamino)ethenyl]-1,6-dihydro-6-oxo-3-pyridinecarbonitrile,m.p.154°-155° C., was prepared as in Example 2 but using an excess ofdi-n-propylamine in place of diethylamine.

4. 5-Bromo-1,6-naphthyridin-2(1H)-one

Hydrogen bromide was bubbled for about 25 minutes into a stirredsuspension containing 9.5 g of2-[2-(dimethylamino)ethenyl]-1,6-dihydro-6-oxo-3-pyridinecarbonitrile in400 ml of chloroform cooled in an ice bath. The reaction mixture wasstirred in the ice bath for 1 hour, allowed to warm up to roomtemperature and stirred at room temperature overnight. A tlc analysisusing 7:2:1 of diethyl ether: methanol:triethylamine showed onlystarting material and no final product. To the reaction mixture wasadded 150 ml of acetic acid and hydrogen bromide was bubbled into thereaction mixture at room temperature with stirring whereupon thereaction mixture turned a lighter yellow color. The reaction mixture wasthen stirred at room temperature overnight and then concentrated on arotary evaporator to dryness. The residue was stirred in an ice bathwith about 300 ml of 10% aqueous potassium carbonate. The solid wascollected by filtering the mixture through a sintered glass funnel,washed with water and dried in a vacuum oven at 50° C. to yield 10.5 gof 5-bromo-1,6-naphthyridin-2(1H)-one, m.p. 278°-280° C.

In subsequent runs the reaction was run starting with a mixture ofchloroform and acetic acid, illustrated as follows: Into a mixturecontaining 40 g of2-[2-(dimethylamino)ethenyl]-1,6-dihydro-6-oxo-3-pyridinecarbonitrile,400 ml of chloroform and 202 ml of acetic acid, the mixture chilled inan ice bath, was bubbled hydrogen bromide for 45 minutes whereupon thereaction mixture changed from dark yellow to off white. The reactionmixture was stirred in the ice bath for 15 minutes, allowed to warm upto room temperature and then stirred at room temperature over theweekend. The precipitate was collected, washed with chloroform and driedin vacuum oven at 60° C. to yield 83 g of solid which contained someinorganic material. The solid was slurried in water along with theconcentrate obtained by evaporating the mother liquor on a rotaryevaporator and the mixture was stirred at room temperature. The solidwas collected, washed with water and dried in a vacuum oven at 90° C. toyield 41.2 g of 5-bromo-1,6-naphthyridin-2(1H)-one, m.p. 272°-274° C.

Acid-addition salts of 5-bromo-1,6-naphthyridin-2(1H)-one areconveniently prepared by adding to a mixture of 2 g of5-bromo-1,6-naphthyridin-2(1H)-one in about 40 ml of aqueous methanolthe appropriate acid, e.g., methanesulfonic acid, concentrated sulfuricacid, concentrated phosphoric acid, to a pH of about 2-3, chilling themixture after partial evaporation and collecting the precipitate, e.g.,dimethanesulfonate, sulfate, phosphate respectively. Also, theacid-addition salt is conveniently prepared in aqueous solution byadding to water with stirring molar equivalent quantities of5-bromo-1,6-naphthyridin-2(1H)-one and the appropriate acid, e.g.,lactic acid or hydrochloric acid, to prepare respectively themonolactate or monohydrochloride salt in aqueous solution.

Cationic salts of 5-bromo-1,6-naphthyridin-2(1H)-one are convenientlyprepared by reaction with an equivalent quantity of the appropriatebase, e.g., sodium hydroxide, potassium hydroxide or tetramethylammoniumhydroxide, to produce the corresponding respective sodium, potassium ortetramethylammonium salt. The salts are prepared in solution or in solidform by suspending equivalent quantities of5-bromo-1,6-naphthyridin-2(1H)-one and base in water or water-methanolto form the solution of salt or by evaporating the solvent from thesolution to obtain the salt in solid form.

5. 5-Chloro-1,6-naphthyridin-2(1H)-one

Following the procedure described in Example 4 using a molar equivalentquantity of hydrogen chloride in place of hydrogen bromide, it iscontemplated that 5-chloro-1,6-naphthyridin-2(1H)-one can be obtained.

6. 5-(1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one

To a solution containing 15 g of imidazole dissolved in 200 ml ofdimethylformamide was added with stirring 2.7 g of sodium hydride andthe resulting mixture stirred at room temperature for 10 minutes. To thereaction mixture was then added 11.3 g of5-bromo-1,6-naphthyridin-2(1H)-one and the reaction mixture was refluxedovernight. The reaction mixture was concentrated on a rotary evaporatorto remove most of the solvent. To the concentrate was added water plus7.5 ml of concentrated hydrochloric acid and the mixture allowed tostand at room temperature. The solid that separated was collected,washed successively with water and n-hexane, and dried in a vacuum ovenat 90° C. to yield 4.5 g of off-white powder. The powder wasrecrystallized from hot methanol, washed with methanol and dried in avacuum oven at 90° C. to yield 4.0 g of5-(1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, m.p. 291°-292° C.

Acid-addition salts of 5-(1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-oneare conveniently prepared by adding to a mixture of 2 g of5-(1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one in about 40 ml ofaqueous methanol the appropriate acid, e.g., methanesulfonic acid,concentrated sulfuric acid, concentrated phosphoric acid, to a pH ofabout 2 to 3, chilling the mixture after partial evaporation andcollecting the precipitate, e.g., dimethanesulfonate, sulfate,phosphate, respectively. Also, the acid-addition salt is convenientlyprepared in aqueous solution by adding to water with stirring molarequivalent quantities of 5-(1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-oneand the appropriate acid, e.g., lactic acid or hydrochloric acid, toprepare respectively the monolactate or monohydrochloride salt inaqueous solution.

Cationic salts of 5-(1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one areconveniently prepared by reaction with an equivalent quantity of theappropriate base, for example, sodium hydroxide, potassium hydroxide,ethylamine, trimethylamine or tetramethylammonium hydroxide, to form thecorresponding respective sodium, potassium, ethylammonium,trimethylammonium or tetramethylammonium salt. The salts are prepared insolution or in solid form by suspending a equivalent quantities of said5-(1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one and base in water orwater-methanol to form the solution of salt or by evaporating thesolvent from the solution to obtain the salt in solid form.

7. 5-(4-Methyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one

A mixture containing 6.75 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 7.0 gof 4-methyl-1H-imidazole and 100 ml of dimethylformamide was refluxedwith stirring for 33 hours and then concentrated on a rotary evaporator.The residue was slurried in water, the mixture treated with a smallquantity of acetic acid. The solid was collected, washed with water anddried in a vacuum oven at 90° C. The solid was dissolved in boilingisopropyl alcohol, the hot solution treated with decolorizing charcoaland filtered. The hot filtrate was concentrated and cooled. Theseparated solid was collected, washed successively with isopropylalcohol and ether and dried in a vacuum oven at 90° C. to yield 1.9 g ofproduct which was recrystallized a second time from isopropyl alcoholand dried under reduced pressure at 105° C. to yield 1.1 g of5-(4-methyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one as a compoundwith 2-propanol (4:1) and water (4:1), m.p. 257°-259° C.

A 19.6 g portion of5-(4-methyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one as a compoundwith one-fourth mole each of isopropyl alcohol and water per mole ofsaid compound was recrystallized from 1.3 liters of ethanol and therecrystallized solid was dried at 115° C. in a drying pistol(Abderhalden) at <1 mm pressure for two days. The resulting compound,weighing 15.1 g, contained one-fourth mole of ethanol per mol of saidcompound. This 15.1 g portion was recrystallized from about 2500 ml ofwater and dried at 125° C. in a drying pistol at <1 mm pressure forthree days to produce 12.0 g of5-(4-methyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, m.p. 263°-264°C.

Acid-addition salts and cationic salts of5-(4-methyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one are prepared asin Example 6 following the procedures described therein.

8. 5-(2-Methyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one

A mixture containing 5.6 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 8 g of2-methyl-1H-imidazole, 25 ml of N-methylpyrrolidinone, 3.4 g ofanhydrous potassium carbonate and 50 mg of copper powder was refluxedfor 6 hours, allowed to cool to room temperature and then poured into100 ml of water. The resulting solution was neutralized by adding aceticacid and the resulting solution was allowed to stand overnight at roomtemperature. The solid that separated was collected, recrystallized fromdimethylformamide and dried in a vacuum oven at 90°-95° C. to yield 2.4g of 5-(2-methyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one,m.p. >310° C.

9. 5-(2-Methyl-5-nitro-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one

A mixture containing 5.6 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 12.7 gof 2-methyl-5-nitro-1H-imidazole, 3.45 g of anhydrous potassiumcarbonate and 50 ml of N-methylpyrrolidinone was refluxed for 5.5 hours,cooled and concentrated in vacuo to remove most of the solvent. To theconcentrate was added 100 ml of water and 10 ml of 35% aqueous sodiumhydroxide; and, the mixture was treated with decolorizing charcoal andfiltered. The filtrate was acidified with acetic acid and theprecipitate was collected, washed with water, dried, recrystallized fromdimethylformamide, and dried in a vacuum oven at 90°-95° C. to yield 4.5g of 5-(2-methyl-5-nitro-1H-imidazol-1-yl)-1,6-naphthyridin-2-(1H)-one,m.p. >300° C.

10. 5-(1H-pyrazol-1-yl)-1,6-naphthyridin-2-(1H)-one

To a mixture containing 5-hydrazino-1,6-naphthyridin-2(1H)-onemonohydrochloride monohydrate suspended in 100 ml of methanol was added1.35 g of sodium methoxide and the mixture stirred at room temperaturefor 20 minutes and then stripped to dryness in vacuo to produce5-hydrazino-1,6-naphthyridin-2(1H)-one in free base form. To the residuewas added 6.15 g of 1,1,3,3-tetramethoxypropane and 25 ml of ethyleneglycol; and, the resulting mixture was heated with stirring to about170° C., allowing the methanol boil off from the reaction mixture. Thereaction mixture was allowed to stand at room temperature over theweekend and was then concentrated on a rotary evaporator. The residuewas slurried in boiling methanol; and, the mixture was cooled andfiltered. The solid was slurried in water, collected and dried in avacuum oven at about 90° C. The solid was dissolved in boilingdimethylformamide, the hot solution treated with decolorizing charcoaland filtered, and, the filtrate allowed to cool. The separated productwas collected, washed with methanol and dried in a vacuum oven at 90° C.to yield 2.8 g of 5-(1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one,m.p.>300° C.

Acid-addition salts of 5-(1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-oneare conveniently prepared by adding to a mixture of 2 g of5-(1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one in about 40 ml of aqueousmethanol the appropriate acid, e.g., methanesulfonic acid, concentratedsulfuric acid, concentrated phosphoric acid, to a pH of about 2 to 3,chilling the mixture after partial evaporation and collecting theprecipitate, e.g., dimethanesulfonate, sulfate, phosphate, respectively.Also, the acid-addition salt is conveniently prepared in aqueoussolution by adding to water with stirring molar equivalent quantities of5-(1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one and the appropriate acid,e.g., lactic acid or hydrochloric acid, to prepare respectively themonolactate or monohydrochloride salt in aqueous solution.

Cationic salts of 5-(1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one areconveniently prepared by reaction with an equivalent quantity of theappropriate base, for example, sodium hydroxide, potassium hydroxide ortetramethylammonium hydroxide, to form the corresponding respectivesodium, potassium or tetramethylammonium salt. The salts are prepared insolution or in solid form by suspending a equivalent quantities of said5-(1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one and base in water orwater-methanol to form the solution of salt or by evaporating thesolvent from the solution to obtain the salt in solid form.

The above intermediate 5-hydrazino-1,6-naphthyridin-2(1H)-one as itsmonohydrochloride monohydrate was prepared as follows. A mixturecontaining 30 g of 5-bromo-1,6-naphthyridin-2(1H)-one and 20.2 ml ofhydrazine hydrate was heated to reflux and then heated for an additional2 hours. The reaction mixture was concentrated on a rotary evaporatorand the residue was slurried in concentrated hydrochloric acid. Thesolid was collected, washed with concentrated hydrochloric acid, driedin a vacuum oven at 75° C. The solid was then slurried in water,collected by filtration, washed with water and dried in a vacuum oven at90° C. to yield 25.2 g of 5-hydrazino-1,6-naphthyridin-2(1H)-onemonohydrochloride monohydrate, m.p.>310° C. with decomposition.

11. 5-(1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one

A mixture containing 5.6 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 100 mlof dimethylformamide and 6.9 g of 1,2,4-triazole was refluxed on an oilbath for 21 hours and then allowed to cool. The separated solid wascollected, washed with ethanol and dried in a vacuum oven at 90° C. toyield 2.8 g of 5-(1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one,m.p.>300° C.

Acid-addition salts of5-(1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one are convenientlyprepared by adding to a mixture of 2 g of5-(1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one in about 40 ml ofaqueous methanol the appropriate acid, e.g., methanesulfonic acid,concentrated sulfuric acid, concentrated phosphoric acid, to a pH ofabout 2 to 3, chilling the mixture after partial evaporation andcollecting the precipitate, e.g., dimethanesulfonate, sulfate,phosphate, respectively. Also, the acid-addition salt is convenientlyprepared in aqueous solution by adding to water with stirring molarequivalent quantities of5-(1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one and the appropriateacid, e.g., lactic acid or hydrochloric acid, to prepare respectivelythe monolactate or monohydrochloride salt in aqueous solution.

Cationic salts of 5-(1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-oneare conveniently prepared by reaction with an equivalent quantity of theappropriate base, for example, sodium hydroxide, potassium hydroxide ortetramethylammonium hydroxide, to form the corresponding respectivesodium, potassium or tetramethylammonium salt. The salts are prepared insolution or in solid form by suspending a equivalent quantities of said5-(1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one and base in wateror water-methanol to form the solution of salt or by evaporating thesolvent from the solution to obtain the salt in solid form.

12. 5-(4,5-Dimethyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one

A mixture containing 12.5 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 300ml of dimethylformamide, 13.8 g of anhydrous potassium carbonate, 10.8 gof 4,5-dimethylimidazole and 200 mg of cuprous bromide was refluxed withstirring for eight hours About 20 ml of the solvent was distilled offusing a water separator to remove any moisture from the reactionmixture. The remaining reaction mixture was concentrated on a rotaryevaporator. The residue was dissolved in water, acidified with aceticacid and evaporated to dryness on a rotary evaporator. The residue wastreated with 50 ml of water and the brown solid was collected, washedwith water, recrystallized from ethanol in the presence of decolorizingcharcoal. The resulting pale yellow solid was dried at 80°-85° C. toyield 6.4 g of5-(4,5-dimethyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, m.p.256°-258° C.

13. 5-(4-Phenyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one

A mixture containing 11.3 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 18 gof 4-phenylimidazole and 500 ml of dimethylformamide was refluxed withstirring for ninety hours and the solvent then distilled off in vacuo.The gummy residue was slurried with a mixture of 250 ml of water and 250ml of ether until no gum remained. The remaining solid was collected,washed successively with water and ethanol, and dried in vacuo at 85° C.to yield 10.8 g of solid. This solid was suspended in 375 ml of boilingabsolute ethanol and dissolved using a small amount of hotdimethylformamide. The solution was allowed to cool in a refrigeratorovernight. The white solid was collected, washed with a small quantityof cold absolute ethanol and dried in vacuo at 90° C. to yield 5.0 g of5-(4-phenyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, m.p. 263°-265°C. Another 1.9 g of product, m.p. 263°-265° C., was obtained from themother liquor.

Following the procedure described in Example 4 but using in place ofimidazole a corresponding molar equivalent quantity of the appropriatesubstituted 1H-imidazole, it is contemplated that the compounds ofExamples 14-24 can be obtained.

14. 5-(2,4-Dimethyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, using2,4-dimethyl-1H-imidazole.

15. 5-(2,4,5-Trimethyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one,using 2,4,5-trimethyl-1H-imidazole.

16. 5-(4-Methyl-5-nitro-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one,using 4-methyl-5-nitro-1H-imidazole.

17.5-(2,4-Dimethyl-5-nitro-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one,using 2,4-dimethyl-5-nitro-1H-imidazole.

18. 5-(2-Ethyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, using2-ethyl-1H-imidazole.

19. 5-(2-Isopropyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, using2-isopropyl-1H-imidazole.

20. 5-(4-Ethyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, .using4-ethyl-1H-imidazole

21. 5-(4,5-Diethyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, using4,5-diethyl-1H-imidazole

22.5-(2-Methyl-4,5-di-n-propyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one,using 2-methyl-4,5-di-n-propyl-1H-imidazole.

23. 5-(4-Tert-butyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, using4-tert-butyl-1H-imidazole.

24. 5-(4,5-Di-n-butyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one,using 4,5-di-n-butyl-1H-imidazole.

Following the procedure described in Example 4 but using a molarequivalent quantity of the corresponding substituted-1-H-pyrazole inplace of imidazole, it is contemplated that the compounds of Examples25-32 can be obtained.

25. 5-(3,4-Dimethyl-1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one, using3,4-dimethyl-1H-pyrazole.

26. 5-(3,5-Dimethyl-1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one, using3,5-dimethyl-1H-pyrazole.

27. 5-(3-Methyl-1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one, using3-methyl-1H-pyrazole.

28. 5-4-Methyl-1H-pyrazol-1-yl)-1,6-naphthyridin-(1H)-one, using4-methyl-1H-pyrazole.

29. 5-(3,4,5-Trimethyl-1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one,using 3,4,5-trimethyl-1H-pyrazole.

30. 5-(4-Ethyl-3,5-dimethyl-1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one,using 4-ethyl-3,5-dimethyl-1H-pyrazole.

31. 5-(3-n-Propyl-1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one, using3-n-propyl-1H-pyrazole.

32. 5-(3-Phenyl-1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one, using3-phenyl-1H-pyrazole.

Following the procedure described in Example 6 using a molar equivalentquantity of the appropriate substituted-1H-1,2,4-triazole in place of1H-imidazole, it is contemplated that the compounds of Examples 33-39can be obtained.

33. 5-(3,5-Dimethyl-1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one,using 3,5-dimethyl-1H-1,2,4-triazole.

34. 5-(5-Methyl-1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one, using5-methyl-1H-1,2,4-triazole.

35. 5-(3-Methyl-1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one, using3-methyl-1H-1,2,4-triazole.

36. 5-(3-Phenyl-1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one, using3-phenyl-1H-1,2,4-triazole.

37. 5-(3-Ethyl-1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one, using3-ethyl-1H-1,2,4-triazole.

38. 5-(3-n-Propyl-1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one,using 3-n-propyl-1H-1,2,4-triazole.

39. 5-(3,5-Diethyl-1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H) -one,using 3,5-diethyl-1H-1,2,4-triazole.

40. 5-(3-Methyl-1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one

A stirred mixture containing 13.5 g of5-bromo-1,6-naphthyridin-2(1H)-one, 18 ml of 3-methyl-1H-pyrazole and 75ml of N-methylpyrrolidinone was heated in an oil bath at 170°-180° C.for 18 hours, after which a tlc analysis indicated some remainingstarting material. The temperature of the oil bath was raised to 200°C.; and, the reaction mixture was heated for an additional 5 hours andthen poured into water. The solid that separated was collected, driedand combined with 1.7 g of corresponding material obtained in anotherrun starting with 2.25 g of 5-bromo-1,6-naphthyridin-2(1H)-one. Thecombined solids were recrystallized from dimethylformamide and dried inan oven for three days at 100° C. to yield 6.6 g of5-(3-methyl-1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one, m.p. >300° C.

41. 5-(3-Methyl-1H-1,2,4-triazole-1-yl)-1 ,6-naphthyridin-2-(1H)-one

A stirred mixture containing 13.5 g of5-bromo-1,6-naphthyridin-2(1H)-one, 20 g of 3-methyl-1H-1,2,4-triazoleand 75 ml of N-methylpyrrolidinone was heated in an oil bath at170°-180° C. for 18 hours and then cooled to room temperature whereupona tan solid crystallized out. The mixture was diluted by adding 125 mlof water and the separated solid was collected, washed with water,air-dried and combined with another 1.2 g sample of the same materialobtained in another run starting with 2.25 g of5-bromo-1,6-naphthyridin-2(1H)-one. The combined solids wererecrystallized from dimethylformamide and dried in an oven at 95°-100°C. for three days to yield 6.1 g of5-(3-methyl-1H-1,2,4-triazole-1-yl)-1,6-naphthyridin-2(1H)-one,m.p. >300° C.

42. 5-[4-(Hydroxymethyl)-1H-imidazol-1-yl]-1,-6-naphthyridin-2(1H)-one

A mixture containing 22.5 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 31.4g of 4-(hydroxymethyl)-1H-imidazole and 75 ml of N-methylpyrrolidinonewas heated with stirring in an oil bath at 135°-150° C. for 38 hours.The reaction mixture was cooled to room temperature, diluted with waterand when no precipitate separated the dark solution was filtered. Thefiltrate was concentrated in vacuo to yield a brown viscous oil whichwas further concentrated on a rotary evaporator to yield a brownsemi-solid. Residual N-methylpyrrolidinone was removed by heating thesemi-solid residue under reduced pressure in an oil bath heated at120°-130° C. to yield 75.4 g of a semi-solid. To this material was added50 ml of water and the mixture was allowed to stand at room temperaturefor two days whereupon some light orange product crystallized. Thismaterial was collected, washed with cold water and dried. This materialwas recrystallized several times from water and finally from methanol,and dried in an oven at 90°-95° C. to yield 4.5 g of5-[4-(hydroxymethyl)-1H-imidazol-1-yl]-1,6-naphthyridin-2(1H)-one, m.p259°-261° C.

43. 5-(4-Bromo-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one

A stirred mixture containing 11.25 g of5-bromo-1,6-naphthyridin-2(1H)-one, 16.6 g of 4-bromo-1H-imidazole and100 ml of N-methylpyrrolidinone was heated in an oil bath at 135°-140°C. for 22 hours. The reaction mixture was cooled and diluted with 200 mlof water. The resulting precipitate was collected, washed with water,air-dried, combined with 1.5 g of5-(4-bromo-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one prepared inanother run starting with 1 58 g of 5-bromo-1,6-naphthyridin-2(1H)-one,recrystallized twice from dimethylformamide and dried in an Abderhaldendrying pistol at 90° for 22 hours, after which the sample stillcontained 0.2 mol of dimethylformamide per mol of product. The materialwas then dissolved in 100 ml of 5% aqueous sodium hydroxide solution,the solution filtered and the filtrate solidified with acetic acid. Thecottony solid that crystallized out was collected, washed with distilledwater and dried in an oven at 100° C. over the weekend to produce 10.3 gof 5-(4-bromo-1H-imidazol-1-yl)- 1,6-naphthyridin-2(1H)-one, m.p.278°-280° C.

44.5-[(4-(Trifluoromethyl)-1H-imidazol-1-yl)]-1,6-naphthyridin-2(1H)-one

A stirred mixture containing 2.25 g of5-bromo-1,6-naphthyridin-2(1H)-one, 4.1 g of4-(trifluoromethyl)-1H-imidazole, 4.15 g of potassium carbonate in 100ml of dimethylformamide was refluxed for 12 hours and then allowed tocool to room temperature. The insoluble inorganic material was filteredoff and the filtrate was concentrated in vacuo to yield a brown gummyresidue which was dissolved in 150 ml of acetonitrile, the solutiontreated with decolorizing charcoal and filtered, and then the filtrateconcentrated to a volume of about 75 ml. The solution waschromatographed on silica gel using ether:methanol:triethylamine mixture(7:2:1) as the eluant to yield 1.1 g of the crude product.

The above preparation was repeated but changing the heating period from12 hours to 39 hours and following the workup as above, 800 mg of thecrude product was obtained.

In a third run a mixture containing 3.5 g of5-bromo-1,6-naphthyridin-2(1H)-one, 8.5 g of4-(trifluoromethyl)-1H-imidazole, 8.7 g of potassium carbonate and 150ml of dimethylformamide was refluxed with stirring for 29 hours andfollowing a work-up procedure as described in the preceding paragraphs,1.9 g of the crude product was obtained. The three fractions of productwere combined, recrystallized three times from isopropyl alcohol anddried in an oven at 100° C. for two days to yield 1.95 g of5-[(4-trifluoromethyl)-1H-imidazol-1-yl)]-1,6-naphthyridin-2(1H)-one,m.p. 216°-218° C.

45. 2-[2-(Dimethylamino)-1-propenyl]-6-methoxy-3-pyridinecarbonitrile

A mixture containing 47.2 g of6-methoxy-2-methyl-3-pyridinecarbonitrile, 100 ml of dimethylacetamidedimethyl acetal and 100 ml of dimethylformamide was heated with stirringin an oil bath at 130° C. for 1 hour and 45 minutes. The temperature ofthe oil bath was raised to 150° C. and the methanol formed by thereaction was distilled off using a 12" distillation column (Vigreux)while continuing the heating at 150° C. for 14 hours. The reactionmixture was concentrated, 50 ml of ether was added to the concentratedsolution whereupon the product crystallized out. The mixture was chilledand the crystalline solid collected. The solid was washed with coldether, dried and recrystallized from ethyl acetate using decolorizingcharcoal to yield 33.5 g of2-[2-(dimethylamino)-1-propenyl]-6-methoxy-3-pyridinecarbonitrile, m.p.103°-104° C.

The above intermediate 6-methoxy-2-methyl-3-pyridinecarbonitrile wasprepared as follows. A 69 g portion of6-chloro-2-methyl-3-pyridinecarbonitrile was dissolved in 700 ml of warmmethanol. To the solution was added with stirring 27 g of sodiummethoxide whereupon an exothermic reaction ensued. After allowing thesolution to cool, an additional 5 g of sodium methoxide was added andthe mixture was refluxed for 15 minutes. The precipitated sodiumchloride was filtered off and to the filtrate was added about 400 ml ofether, the ether solution treated with decolorizing charcoal andfiltered. The filtrate was evaporated to dryness in vacuo to yield 64 gof 6-methoxy-2-methyl-3-pyridinecarbonitrile, m p. 80°-80.5° C.

46. 5-Bromo-7-methyl-1,6-naphthyridin-2(1H)-one

Into a solution containing 10.8 g of2-[2-(dimethylamino)-1-propenyl]-6-methoxy-3-pyridinecarbonitriledissolved in a mixture of 25 ml of acetic acid and 150 ml of chloroformcooled in an ice-ethanol bath was bubbled hydrogen bromide gas, keepingthe reaction mixture below 20° C. A solid separated and the mixture wasstirred at ambient temperature for 2 hours. The solid(5-bromo-2-methoxy-7-methyl-1,7-naphthyridine) was collected, dried,suspended in 200 ml of water and neutralized by stirring with about 20ml of 2N aqueous potassium hydroxide solution. The separated product wascollected, dried and recrystallized from dimethylformamide to yield 9.0g of 5-bromo-7-methyl-1,6-naphthyridin-2(1H)-one, m.p. 276°-278° C.

47. 7-Methyl-5-(4-methyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one

A mixture containing 9.56 g of5-bromo-7-methyl-1,6-naphthyridin-2(1H)-one, 8.2 g of4-methyl-1H-imidazole and 22 ml of N-methylpyrrolidin-one was heatedwith stirring in an oil bath at 140° C. for 20 hours. The reactionmixture containing some separated solid was diluted with about 150 ml ofwater and the solid was collected, triturated with water, washed withethanol and dried to give 6.0 g of7-methyl-5-(4-methyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, m.p.307°-308° C.

48. 5-(4-Nitro-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one

A stirred mixture containing 13.2 g of5-bromo-1,6-naphthyridin-2(1H)-one, 20.4 g of 4-nitro-1H-imidazole and50 ml of N-methylpyrrolidinone was heated for eight hours in an oil bathat 170°-180° C. The reaction mixture was cooled and diluted with 200 mlof water. The solid that separated was collected, washed with water anddried. The dried solid was dissolved in 350 ml of boilingdimethylformamide, the hot solution treated with decolorizing charcoaland filtered, and the filtrate concentrated on a rotary evaporator. Theresidue was recrystallized from dimethylformamide, dried in an oven at90°-95° C. over the weekend to give 20.4 g of product containing somestarting 4-nitro-1H-imidazole. The mixture was treated with 400 ml of 5%aqueous potassium carbonate solution for thirty minutes and thenfiltered. The insoluble material was filtered off and washed with water.The washings and filtrate were combined and acidified with acetic acid.The solid that separated was collected, washed with water, air-dried andrecrystallized from dimethylformamide to yield 6.8 g of5-(4-nitro-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, m.p. 298°-300°C.

Following the procedure described in Example 43 but using in place of4-bromo-1H-imidazole a molar equivalent quantity of the correspondingappropriate substituted 1H-imidazole, it is contemplated that thefollowing compounds of Examples 49-51 can be obtained.

49. 5-(4-Chloro-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, using4-chloro-1H-imidazole.

50. 5-(4-Chloro-5-methyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one,using 4-chloro-5-methyl-1H-imidazole.

51.5-(2-Bromo-4,5-dimethyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one,using 2-bromo-4,5-dimethyl-1H-imidazole.

Following the procedure described in Example 40 but using in place of3-methyl-1H-pyrazole a molar equivalent quantity of the correspondingappropriate substituted 1H-pyrazole, it is contemplated that thecompounds of Examples 52-55 can be obtained.

52. 5-(4-Nitro-1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one, using4-nitro-1H-pyrazole.

53. 5-(4-Chloro-1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one, using4-chloro-1H-pyrazole.

54. 5-(4-Hydroxymethyl-1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one,using 4-hydroxymethyl-1H-pyrazole.

55. 5-(3-Trifluoromethyl-1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one,using 3-trifluoromethyl-1H-pyrazole.

Following the procedure described in Example 41 but using in place of3-methyl-1H-1,2,4-triazole a molar equivalent quantity of thecorresponding appropriate substituted-1H-1,2,4-triazole, it iscontemplated that the compounds of Examples 56-60 can be obtained.

56. 5-(3-Bromo-1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one, using3-bromo-1H-1,2,4-triazole.

57.5-(3-Bromo-5-methyl-1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one,using 3-bromo-5-methyl-1H-1,2,4-triazole.

58. 5-(5-Chloro-1H-1,2.4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one, using5-chloro-1H-1,2,4-triazole.

59. 5-(3-Nitro-1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one, using3-nitro-1H-1,2,4-triazole.

605-(3-Trifluoromethyl-1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one,using 3-trifluoromethyl-1H-1,2,4-triazole.

61. Following the procedure described in Example 10 but using in placeof 5-hydrazino-1,6-naphthyridin-2(1H)-one a molar equivalent quantity of5-hydrazino-7-methyl-1,6-naphthyridin-2(1H)-one, it is contemplated that7-methyl-5-(1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one can be obtained.The intermediate 5-hydrazino-7-methyl-1,6-naphthyridin-2(1H)-one can beprepared by the procedure described in Example 10 for preparing5-hydrazino-1,6-naphthyridin-2(1H)-one but using a molar equivalentquantity of 5-bromo-7-methyl-1,6-naphthyridin-2(1H)-one in place of5-bromo-1,6-naphthyridin-2(1H)-one.

The usefulness of the compounds of formulas I and II as cardiotonicagents is demonstrated by their effectiveness in standardpharmacological test procedures, for example, in causing a significantincrease in contractile force of the isolated cat or guinea pig atriaand papillary muscle and/or in causing a significant increase in cardiaccontractile force in the anesthetized dog with lower or minimal changesin heart rate and blood pressure. Detailed descriptions of these testprocedures appear in U.S. Pat. No. 4,072,746, issued Feb. 7, 1980.

Cardiotonic activity in said isolated cat or guinea pig atria andpapillary muscle procedure, is indicated by a significant increase, thatis, greater than 25% (cat) or 30% (g.pig) in papillary muscle force anda significant increase, that is, greater than 25% (cat) or 30% (g.pig)in right atrial force, with a lower percentage increase (about one-halfor less than the percentage increase in right atrial force or papillarymuscle force) in right atrial rate. Because of the lower control activetensions of guinea pig tissues, the percent change from control valuesof both rate and force responses is elevated slightly, i.e., 5%. Thus,whereas cardiotonic activity is ascertained with a papillary muscleforce or right atrial force increase of 26% and greater in the cat test,corresponding activity in the guinea pig test is designated with apapillary muscle force (PMF) or right atrial force (RAF) increase of 31%or greater. Representative examples of the compounds of Formulas I andII were tested by said guinea pig atria and papillary muscle procedurewith the following results:

    ______________________________________                                                 Dose  % Change from Control                                          Example    μg/ml                                                                              RAF           PMF                                          ______________________________________                                        6           3      70            55                                                      10      68            90                                                      30      142           96                                           7          0.3     28            53                                                       1      49            66                                                       3      88            87                                           8          10      39            34                                                      30      117           69                                                      100     221           100                                          9          10      15            24                                                      30      16            43                                                      100     116           103                                          10         10      38            43                                                      30      102           121                                                     100     168           203                                          11          3      28            51                                                      10      31            76                                                      30      140           108                                          12          3       7            13                                                      10      14            49                                                      30      50            92                                           13         10      33            25                                                      30      24            34                                                      100      1*           36                                           47          1      37            46                                                       3      46            48                                                      10      158           164                                          42          1      -2             9                                                       3       8            48                                                      10      37            112                                          44         10      35            30                                                      30      36            31                                                      100     101           69                                           43          1      35            47                                                       3      43            71                                                      10      56            128                                          41          1      29            36                                                       3      37            56                                                      10      67            124                                          40          3      26            24                                                      10      89            64                                                      30      84            97                                           4           3      57            73                                                      10      49            85                                                      30      134           110                                          48         10      18            37                                                      30      42            71                                                      100     170           107                                          46          1      41            44                                                       3      92            67                                                      10      59            114                                          ______________________________________                                         *Precipitated in bath.                                                   

When tested by said anesthetized dog procedure, the said cardiotonicallyactive compounds of formulas I and II at doses of from about 0.030 to3.0 mg/kg administered intravenously are found to cause significantincreases, that is, 25% or greater, in cardiac contractile force orcardiac contractility with lower changes in heart rate and bloodpressure. Representative examples of the invention were tested by thisprocedure and found to cause increases in contractile force as follows:

    ______________________________________                                                      Dose    % Increase In                                           Example       mg/kg   Contractile Force                                       ______________________________________                                        4             0.100   135                                                     7             0.030   34                                                                    0.100   96                                                                    0.300   124                                                     12            1.00    54                                                                    3.00    136                                                     13            1.00    40                                                                    3.00    87                                                      47            0.100   71                                                                    0.300   125                                                                   1.00    183                                                     ______________________________________                                    

The present invention includes within its scope a cardiotoniccomposition for increasing cardiac contractility, said compositioncomprising a pharmaceutically acceptable carrier and, as the activecomponent thereof, the compound of formula I or II or pharmaceuticallyacceptable acid-addition or cationic salt thereof. The invention alsoincludes within its scope the method for increasing cardiaccontractility in a patient requiring such treatment which comprisesadministering to such patient a cardiotonically effective amount of saidcardiotonically active compound of formula I or II. In clinical practicesaid compound will normally be administered orally or parenterally in awide variety of dosage forms.

Solid compositions for oral administration include compressed tablets,pills, powders and granules. In such solid compositions, at least one ofthe active compounds is admixed with at least one inert diluent such asstarch, calcium carbonate, sucrose or lactose. These compositions mayalso contain additional substances other than inert diluents, e.g.,lubricating agents, such as magnesium stearate, talc, and the like.

Liquid compositions for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirscontaining inert diluents commonly used in the art, such as water andliquid paraffin. Besides inert diluents such compositions may alsocontain adjuvants, such as wetting and suspending agents, andsweetening, flavoring, perfuming and preserving agents. According to theinvention, the compounds for oral administration also include capsulesof absorbable material, such as gelatin, containing said activecomponent with or without the addition of diluents or excipients.

Preparations according to the invention for parenteral administrationinclude sterile aqueous, aqueous-organic, and organic solutions,suspensions and emulsions. Examples of organic solvents or suspendingmedia are propylene glycol, polyethylene glycol, vegetable oils such asolive oil and injectable organic esters such as ethyl oleate. Thesecompositions can also contain adjuvants such as stablilizing,preserving, wetting, emulsifying and dispersing agents.

They can be sterilized, for example by filtration through abacterial-retaining filter, by incorporation of sterilizing agents inthe compositions, by irradiation or by heating. They can also bemanufactured in the form of sterile solid compositions which can bedissolved in sterile water or some other sterile injectable mediumimmediately before use.

The percentage of active component in the said composition and methodfor increasing cardiac contractility can be varied so that a suitabledosage is obtained. The dosage administered to a particular patient isvariable, depending upon the clinician's judgement using as thecriteria: the route of administration, the duration of treatment, thesize and condition of the patient, the potency of the active componentand the patient's response thereto. An effective dosage amount of activecomponent can thus only be determined by the clinician considering allcriteria and utilizing his best judgement on the patient's behalf.

We claim:
 1. 5-X-7-R'-1,6-naphthyridin-2(1H)-one having the formula II##STR7## or pharmaceutically acceptable or cationic salt thereof, whereX is bromo, chloro or hydrazino and R' is hydrogen or methyl. 2.5-Bromo-1,6-naphthyridin-2(1H)-one according to claim
 1. 3.5-Hydrazino-1,6-naphthyridin-2(1H)-one according to claim
 1. 4.5-Bromo-7-methyl-1,6-naphthyridin-2(1H)-one according to claim
 1. 5. Acardiotonic composition for increasing cardiac contractility whichcomprises a pharmaceutically acceptable carrier and, as the activecomponent thereof, a cardiotonically effective amount of5-X-7-R'-1,6-naphthyridin-2(1H)-one of claim 1 or pharmaceuticallyacceptable acid-addition or cationic salt thereof, where X is bromo orchloro and R' is hydrogen or methyl.
 6. A method for increasing cardiaccontractility in a patient requiring such treatment which comprisesadministering orally or parenterally in a solid or liquid dosage form tosuch patient a cardiotonically effective amount of5-X-7-R'-1,6-naphthyridin-2(1H)-one of claim 1 or pharmaceuticallyacceptable acid-addition or cationic salt thereof, where X is bromo orchloro and R' is hydrogen or methyl.